Project Summary Primary aldosteronism (PA) accounts for >10% of all hypertensive cases and >20% of resistant hypertensive cases. PA substantially increases the risk of cardiovascular and renal disease, independent of blood pressure. Although medical therapy with mineralocorticoid receptor (MR) antagonists is widely recommended as first-line treatment for the majority of cases of PA, almost no long-term data exists on the effectiveness of MR antagonists in improving health outcomes. MR antagonists may be inadequate or not used aggressively enough in practice to effectively block pathologic aldosterone excess as most surgically treated PA cases are cured of hypertension while the vast majority of PA cases treated with MR antagonists require additional antihypertensive medications for blood pressure control. Further, there are no evidence-based recommendations on how best to prescribe and monitor MR antagonists to maximize long-term health benefits. We propose to prospectively examine the associations between MR antagonist therapy in PA and cardiovascular and renal outcomes and to investigate the optimal medical treatment and surveillance strategy in these patients. Using the Partners Research Patient Data Registry, a centralized clinical data repository of ~10 million patients from Brigham and Women's Hospital, Massachusetts General Hospital, and their associated hospitals, we will assemble a cohort of 3,500 cases of PA treated with MR antagonists (exposed group), 1,500 cases of surgically treated PA (comparison group 1), and 10,000 age-, sex-, race-, and blood pressure-matched essential hypertensives (comparison group 2). In Aim 1, we will study MR antagonist use in PA and incident cardiovascular disease. We hypothesize that there will be a higher risk of incident cardiovascular disease, independent of blood pressure, in PA treated with MR antagonists compared with: a) surgically treated PA and b) treated essential hypertension. In Aim 2, we will study MR antagonist use in PA and rate of estimated glomerular filtration rate (eGFR) decline. We hypothesize that there will be a faster eGFR decline, independent of blood pressure, in PA treated with MR antagonists compared with: a) surgically treated PA and b) treated essential hypertension. In Aim 3, we will evaluate whether renin activity can serve as a clinically informative biomarker to guide titration of MR antagonist therapy in PA. We hypothesize that PA patients with higher renin activity while on MR antagonists will require fewer antihypertensive medications and have a lower risk of incident cardiovascular disease compared with PA patients with lower renin activity while on MR antagonists. This study may have immediate and direct implications on the management of PA by: a) elucidating whether MR antagonists are adequate at effectively blocking pathologic aldosterone excess and reducing the risk of adverse health outcomes and b) evaluating whether renin activity can serve as a biomarker in clinical practice to guide MR antagonist titration.